Nucleoside phosphonates have antiviral, antiproliferative and a variety of other therapeutic benefits. Among these are the antiviral nucleoside phosphonates, such as, for example, cidofovir, cyclic cidofovir, adefovir, tenofovir, and the like, as well as the 5′-phosphonates and methylene phosphonates of azidothymidine (AZT), ganciclovir, acyclovir, and the like. In these compounds, the 5′-hydroxyl of the sugar moiety, or its equivalent in acyclic nucleosides (ganciclovir, penciclovir, acyclovir) which do not contain a complete sugar moiety, is replaced with a phosphorus-carbon bond. In the case of the methylene phosphonates, a methylene group replaces the 5′-hydroxyl or its equivalent, and its carbon atom is, in turn, covalently linked to the phosphonate.
Upon cellular metabolism of nucleoside phosphonates, two additional phosphorylations occur to form the nucleoside phosphonate diphosphate which represents the equivalent of nucleoside triphosphates. Antiviral nucleoside phosphonate diphosphates are selective inhibitors of viral RNA or DNA polymerases or reverse transcriptases. That is to say, their inhibitory action on viral polymerases is much greater than their degree of inhibition of mammalian cell DNA polymerases α, β and γ or mammalian RNA polymerases. Conversely, the antiproliferative nucleoside phosphonate diphosphates inhibit cancer cell DNA and RNA polymerases and may show much lower selectivity versus normal cellular DNA and RNA polymerases.
As noted above, one class of antiviral and antiproliferative compounds are the antiviral nucleoside phosphonates. Two representative structures of this class of compounds, namely CDV and HPMPA, are set forth below:

Another class of phosphonates is the 5′-phosphonates and methylene phosphonates of azidothymidine, ganciclovir, acyclovir, and the like. In compounds of this type, the 5′-hydroxyl of the sugar moiety, or its equivalent in acyclic nucleosides (ganciclovir, penciclovir, acyclovir), which do not contain a complete sugar moiety, is replaced with a phosphorus-carbon bond. In the case of the methylene phosphonates, a methylene group replaces the 5′-hydroxyl or its equivalent, and its carbon atom is, in turn, covalently linked to the phosphonate. Two representative structures of this class of compounds, namely AZT 5′-phosphate and AZT 5′-phosphonate, are set forth below.

Another class of therapeutically effective compounds is the nucleoside phosphates, such as, acyclovir monophosphate, 2′-O-methyl-guanosine-5′-phosphate, 2′-O-methyl-cytidine-5′-phosphate and 2′-C-methyl-cytidine-5′-phosphate. Two representative structures of this class of compounds are set forth below:

Yet another class is the antiviral phosphonates, phosphonoformate and phosphonoacetate as illustrated below.

Various substituent groups may be attached to phosphonates and phosphates to produce derivatives having various degrees of pharmacological potency. One class of derivative compounds are the alkoxyalkyl esters, such as hexadecyloxypropyl cidofovir (HDP-CDV), which is illustrated by the following general structure:
CDV itself is not orally active; however esterification of CDV with certain alkoxyalkanols such as hexadecyloxypropanol dramatically increases its antiviral activity and selectivity in vitro and confers a degree of oral bioavailability. The alkyl chain length of these CDV analogs is related to solubility and the ability of the compounds to associate with biomembranes.
Although alkoxyalkyl esters of nucleoside phosphates and phosphonates, such as hexadecyloxypropyl-cidofovir (HDP-CDV), have therapeutically beneficial properties, they suffer from pharmacological disadvantages as orally administered agents. Orally administered drugs are usually taken up from the small intestine into the portal vein, which exposes the drug to potentially rapid lipid metabolism in the enterocytes of the small intestines and in the liver. Alkoxyalkyl esters of phosphates and phosphonates, such as HDP-CDV can be incorporated into cell membranes where the phosphate or phosphonate is subsequently liberated inside the cell or can be oxidatively metabolized by the cytochrome P450s such as CYP3A4 in the liver or intestine leading to omega oxidation of the alkyl chain followed by beta oxidation. It has recently been determined that alkoxyalkyl esters of phosphates and phosphonates can be oxidized at the terminal end of the alkyl chain by omega oxidation and are further degraded by beta oxidation to short chain inactive metabolites. This process, which is illustrated in FIG. 1 for nucleoside monophosphonate HDP-CDV, may be very rapid and is deleterious to the intended pharmacologic effect of the compounds. In the case of HDP-CDV, the inactive metabolite is water soluble, virologically inactive, and rapidly excreted in the urine. Rapid metabolism by this pathway may lower plasma levels of the prodrug, and reduce the antiviral efficacy of HDP-CDV and alkoxyalkyl esters of phosphonates, nucleoside phosphonates and nucleoside phosphates.
There is therefore a continuing need for more stable pharmaceutical agents to treat a variety of disorders, such as those caused by viral infection and inappropriate cell proliferation, e.g. cancer. Thus, it is an object of the present invention to develop chemically modified phosphonates, nucleoside phosphonates and nucleoside phosphates that can slow the metabolism of oral antiviral and anticancer compounds.